Technical Note: On the Selection of Precooling Loops for Low-Temperature Continuous Flow Chemistry

Abstract Precooling lines are often used in cryogenic flow chemistry, but factors affecting their performance are not well characterized. We present a systematic study on the effects of flow rate, residence time, and internal diameter on the cooling performance of a selection of tubing commonly used in flow chemistry systems using tetrahydrofuran (THF) and 2-methyl tetrahydrofuran (2-MeTHF) as the solvents. On the basis of our findings, guidelines for minimum residence times for effective precooling are suggested. A general model for precooling was derived and evaluated. The model demonstrates reasonable agreement with experimental values and may be useful for identifying sufficient precooling times for other solvents. The scope and limitations of precooling as a temperature management strategy are explored in a series of lithiation reactions on aryl bromides in a flow. We surmise that, while precooling in flow is important, it is not the only factor relevant in stabilizing extremely reactive species in isolation.